The Principal Investigator proposes to examine the effect of bile acids on cholangiocyte biology, based on the premise that chronic liver diseases with prominent cholestasis may be the result of injury directed towards the epithelial cells lining the biliary tree (cholangiocytes). Increased cholangiocyte secretion and proliferation are hallmarks of bile duct injury, and appear to be adaptive responses to injury. This occurs in the presence of elevated local levels of bile acids. With the recent discovery of the apical bile acid transporter (ABAT) in cholangiocytes, the question arises as to how bile acids modify cholangiocyte biology. The hypothesis is proposed that bile acids are internalized and affect intracellular signaling. The studies will determine the transcriptional regulation, translocation, and activity of ABAT in cholangiocytes; the potential for ABAT promoting the "chole-hepatic shunt" for uptake of bile acids from bile back into the circulation within the liver will also be examined. The effect of bile acids on intracellular PKC, Ca++ and ERK signaling pathways will be determined. The differential effects of endogenous bile acids vs. therapeutic bile acids also will be examined. These studies will provide a better understanding of how bile acids interact with cholangiocytes, and hence may improve understanding of the cholangiocyte adaptation to injury.